Dataset Information

Red Blood Cell-Derived Iron Alters Macrophage Function in COPD.

ABSTRACT: Lung macrophage iron levels are increased in COPD patients. Lung macrophage iron levels are thought to be increased by cigarette smoke, but the role of red blood cells (RBCs) as a source of iron has not been investigated. We investigate RBCs as a potential source of alveolar iron in COPD, and determine the effect of RBC-derived iron on macrophage function. We used lung tissue sections to assess RBC coverage of the alveolar space, iron and ferritin levels in 11 non-smokers (NS), 15 smokers (S) and 32 COPD patients. Lung macrophages were isolated from lung resections (n = 68) and treated with hemin or ferric ammonium citrate (50, 100 or 200 μM). Lung macrophage phenotype marker gene expression was measured by qPCR. The phagocytosis of Non-typeable Haemophilus influenzae (NTHi) was measured by flow cytometry. Cytokine production in response to NTHi in iron-treated macrophages was measured by ELISA. Lung macrophage iron levels were significantly correlated with RBC coverage of the alveolar space (r = 0.31, p = 0.02). Furthermore, RBC coverage and lung macrophage iron were significantly increased in COPD patients and correlated with airflow obstruction. Hemin treatment downregulated CD36, CD163, HLA-DR, CD38, TLR4, CD14 and MARCO gene expression. Hemin-treated macrophages also impaired production of pro-inflammatory cytokines in response to NTHi exposure, and decreased phagocytosis of NTHi (200 μM: 35% decrease; p = 0.03). RBCs are a plausible source of pulmonary iron overload in COPD. RBC-derived iron dysregulates macrophage phenotype and function.

SUBMITTER: Baker JM

PROVIDER: S-EPMC8698324 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundHemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury.MethodsTwo separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann-Whitney test, multiple groups were compared using the Kruskal-Wallis test followed by Dunn's procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables.ResultsHUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis.ConclusionsElevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.

Project description:BackgroundHigher red blood cell distribution width (RDW) levels are associated with mortality in patients with chronic obstructive pulmonary disease (COPD). However, more convincing evidence is still lacking, and the relationship between hemoglobin-to-red blood cell distribution width ratio (HRR) and mortality in patients with COPD remains unclear.MethodsThis study is a prospective cohort study that includes 3,745 adult patients with COPD from the National Health and Nutrition Examination Survey (NHANES) database spanning from 1999 to 2018 in the United States. COX proportional hazards regression analysis, Kaplan-Meier survival curves and restricted cubic spline models were employed to investigate the association of RDW and HRR levels with mortality. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to evaluate the accuracy of RDW and HRR in predicting mortality in patients with COPD.ResultsHigher RDW level was positively associated with increased risk of all-cause mortality (HR = 1.16, 95% CI = 1.11-1.21, P < 0.001), cardiovascular disease (CVD) mortality (HR = 1.13, 95% CI = 1.06-1.21, P < 0.001), and chronic lower respiratory disease (CLRD) related mortality (HR = 1.15, 95% CI = 1.05-1.25, P = 0.003) after adjusting for various potential confounders. HRR was inversely associated with all-cause mortality (HR = 0.14, 95% CI = 0.08-0.25, P < 0.001), CVD mortality (HR = 0.12, 95% CI = 0.05-0.31, P < 0.001). HRR has no significant correlation with CLRD-related mortality. The time-dependent ROC curve showed that RDW exhibited area under the curves (AUCs) of the 5- and 10-year survival rates were 0.707 and 0.714 for all-cause mortality and 0.686 and 0.698, respectively, for CVD mortality. HRR yielded AUCs of the 5- and 10-year survival rates were 0.661 and 0.653 for all-cause mortality and 0.654 and 0.66, respectively, for CVD mortality.ConclusionHigher RDW levels were positively associated with an increased risk of mortality in patients with COPD. HRR levels were negatively correlated with the risk of all-cause and CVD mortality. The predictive value of HRR for mortality in these patients is lower than that of RDW.

Dataset Information

Red Blood Cell-Derived Iron Alters Macrophage Function in COPD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets